IgG and IgM based immunopathological reaction (reaction of

1
IgG and IgM based immunopathological reaction
(reaction of hypersensitivity type II).

• antibody-dependent

• antibodies produced by the immune response bind
  to antigens on the patient's own cell surfaces

• intrinsic ("self" antigen, innately part of the
  patient's cells)

• extrinsic (absorbed onto the cells during
  exposure to some foreign antigen, possibly as
  part of infection with a pathogen)

• These cells are recognized by macrophages or
  dendritic cells which act as antigen presenting
  cells, this causes a B cell response where
  antibodies are produced against the foreign
  antigen.

2
IgG and IgM based immunopathological reaction
(reaction of hypersensitivity type II)

• Autoimmune hemolytic anemia
• Goodpasture's syndrome
• Autoimmune pernicious anemia
• Immune thrombocytopenia
• Transfusion reactions
• Myasthenia gravis
• Rheumatic fever
• Acute transplant rejection

3
Immune complex based immunopathological reaction
(reaction of hypersensitivity type III)

• occurs when antigens and antibodies are present
  in roughly equal amounts, causing extensive
  cross-linking
• large immune complexes that cannot be cleared are
  deposited in vessel walls and induce an
  inflammatory response
• the reaction can take hours, days, or even weeks
  to develop

4
Immune complex based immunopathological reaction
(reaction of hypersensitivity type III)

• Some clinical examples
• Rheumatoid arthritis
• Immune complex glomerulonephritis
• Serum sickness
• Subacute bacterial endocarditis
• Systemic lupus erythematosus
• Farmer's lung (Arthus-type reaction)
• Polyarteritis nodosa

5
PRIMARY IMMUNODEFICIENCY

• clinical manifestactions
• examples

6
IMMUNODEFICIENCY

• Primary immunodeficiencies
• - congenital, genetically defined disorders
• - onset of symptoms - predominantly at an
  early
• age
• Secondary immunodeficiencies
• - caused by chronic infections, irradiation,
  
• injuries, immunosupression therapy,
  surgery,
• stress
• - disorders appear at any age

7
IMMUNIDEFICIENCY

• Humoral deficiency disorders
• the B cell deficiency disorders the
  qualitative or quantitative defects of the B
  cells, present 70 of IDs
• T cell deficiency disorders and the combined
  B-cell and T-cell deficiency disorders (20)
  group of the qualitative or quantitative defects
  of the T and B cells
• Phagocytic cell disorders group of the
  qualitative or quantitative defects of the
  fagocytic cells (10)
• Complement disorders caused by the deficiency
  of the complement components or functions (lt1)

8
MAJOR CLINICAL FEATURES

• Humoral deficiency disorders - manifest as the
  recurrent bacterial sinopulmonary and
  gastrointestinal infections
• - caused by streptococcus, staphylococcus,
  haemophilus, begin when infants are 5-9 months of
  age
• T cell disorders - manifest as the recurrent
  bacterial, fungal and viral respiratory and
  gastrointestinal infection
• Complement disorders are associated with
  increased incidence of the infections and
  autoimmune diseases and with edema in the case of
  hereditary angioedema
• Phagocytic cell disorders characterized by
  recurrent infections caused by various organisms
  incluging abscesses, purulent skin infections,
  granulomatous inflammations

9
HUMORAL DEFICIENCY DISORDERS

• Brutons X-linked hypogamaglobulinemia
• CVID - Common Variable ImmunoDeficiency
• Selective immunoglobulin A deficiency lt0,07 g/l

10
Brutons X-linked hypogamaglobulinemia

• the genetic defect on the X chromosome leads to
  the defective function of a tyrosine kinase in
  the B cells
• This defect result in a block of the pre-B cells
  maturation into the B cells with surface IgM
• the immunologic findings lt 2 circulating B
  cells
• - low serum levels of all
  classes of immunoglobulins
• - number and function of T
  cells are intact
• - pre-B cells are in the bone
  marrow
  
• features begining from 5-9 months of age
  
• - manifests as recurrent bacterial
  sinopulmonary and gastrointestinal infection
  caused by streptococcus, staphylococcus,
  haemophilus, meningococcus, salmonella,
  campylobacter, giardia
• Treatment consists of life-long intravenous
  pooled human gammaglobulin replacement and
  antibiotics.

11
Common Variable ImmunoDeficiency

• the B cell functional disorder characterized by
  the normal number
• of the B cells, low levels of IgG and IgA, a
  poor response to all
• vaccines and decrease of the T cells (CD4)
  number and function
• the symptoms onset between 2nd and 3rd decade
• the clinical features
• - recurrent respiratory tract infections
  (pneumonia), cutaneous and
• gastrointestinal infection
• - disease is accompanied by occurrence of
  the granulomas,
• lymphadenopathy, splenomegaly
• Treatment consist of the intramuscular or
  intravenous
• gammaglobulin replacement.

12
Selective deficiency of IgA

• level of IgA up to 0,05 g/l, age gt 4 years
• the most frequent primary ID
• - stem cell defect
• - repeated infections of respiratory tract
• - susceptibility to autoimmune disorders,
  malignant disorders, allergy
• - contra-indication of administration of drug
  with IgA

13
T cell deficiency disorders

• DiGeorge syndrome
• - the genetic defect on the chromosome 22
  leads to disorder of
• development of 3rd and 4th branchial
  pouch with congenital
• hypoplasia of both the thymus and
  parathyroid glands
• - patients suffer from disorder of
  pre-thymocytes maturation due to
• absence/hypoplasia of thymus
• - syndrome CATCH 22 cardiac defects,
  abnormal facies, thymic
• hypo/aplasia, cleft palate, hypocalcemia,
  deletion 22q11.2
• - the symptoms onset soon after the birth
  hypocalcemic spasms
• and manifestations of congenital heart
  disease
• - treatment symptomatic, transplantation
  of a thymus

14
PRIMARY FAGOCYTIC CELL DEFECTS

• Chronic granulomatous disease
• - X- linked recesive disorder - leads to
  defect in neutrophilic cytochrome b with
  suppresion of intracellular killing of ingested
  microorganisms
• - normal number of leucocytes
• - infection of catalase-positive bacterias
• - symptoms appear in the first year of age
  pyogenic cutaneous
• infections, abscesses, granulomas in many
  organs, pyogenic
• lymphadenitis
• - treatment long-term ATB administration,
  interferon gamma,
• corticosteroids

15
COMPLEMENT DEFICIENCY

• C2, C3, C4 complement components deficiencies
• - lead to an impaired opsonization,
  susceptibility to infections,
• autoimune diseases
• C6, C7, C8, C9 complement components deficiencies
• - lead to the autoimmune diseases SLE,
  RA, sclerodermia and to
• the neisserial infection
• MBL deficiencies
• - lead to the respiratory infections and
  susceptibility to the
• autoimune and allergy diseases
• Treatment vaccination, ATB

16
HEREDITARY ANGIOEDEMA

• pathophysiology
• clinical manifestations
• treatment

17
HEREDITARY ANGIOEDEMA

• the congenital AD complement disorder cased by
  the defect on the chromosome 11
• leads to absence or functional deficiency of
  C1-inhibitor
• C4 a C2 complement components show a low level
• during atack
• Type I - occurs in 85
• - an absence of C1-inhibitor
• Type II - occurs in 15
• - a functional deficiency of
  C1-inhibitor
• Secondary - SLE, lymfoma

18
HEREDITARY ANGIOEDEMA

• C1 esterase inhibitor deficiency leads to
  uncontrolled C1 activity and resultant production
  of a kinin that increases capillary permeability
• Clinical feature transient recurrent localized
  edema
• the triggering factors injuries or
  surgical/stomatological operations
• more offen occures in pregnancy
• laryngeal edema could be life-threatening,
  immediate treatment is necessary !

19
TREATMENT

• Preventive consist of an administration of
  androgens, a-fibrinolytics
• - before operation is necessary C1-INH
  concentrate or a
• fresh frozen plasma administration
• - stomatology procedures are performed in
  hospital
• Immediate - C1-INH concentrate or fresh frozen
  plasma administration
• tracheotomy in severe larynx edema
• treatment with ACE inhibitors is contraindicated

20
ACQUIRED IMMUNODEFICIENCIES

• causes
• mechanisms involved
• AIDS

21
ACQUIRED IMMUNODEFICIENCIES

• Acute and chronic viral infections EBV, CMV,
  herpetic virus, influenza, HIV
• Metabolic disorders diabetes, renal failure,
  disorder of liver function
• Autoimmune diseases autoantibodies against
  immunocompetent cells (neutrophils, lymphocytes)
• Allergic diseases
• Chronic GIT diseases, nephrotic syndrome
• Malignant diseases (leukemia, lymphoma, myeloma)
• Hypersplenism/asplenia, splenectomy deficiency
  in generation of antibodies against encapsulated
  microorganisms (Pneumococcus, Neisseria)
• Burn, postoperative status, injuries
• Severe nutritional disorders, chronic stress
• Drug induced immunodeficiencies (chemotherapy),
  immunosupression
• Chronic exposure to harmful chemical substances,
  ionizing radiation

22
AIDS

• Acquired ImmunoDeficiency Syndrom
• - caused by a retrovirus called human
  immunodeficiency virus
• - current incidence 40 mil.people, predominantly
  in central Africa, CZ about 1000 infected
  people
• viral transmission occurs through
• - sexual intercourse
• - contact with blood
• - transplacentally, during the birth
  process or
• through a breast milk

23
VIRUS HIV-1

• virion is consisted of a capside with marrow
  protein - p24 and RNA
• RNA is copied into double-stranded DNA using
  reverse transcriptase
• virus integrates to the human cell genome and
  arise a provirus
• an activation of provirus leads to the
  replication of viral nuclear acid and genesis of
  a virion that goes through the cell membrane and
  caused the lysis of cell

24
PRIMARY INFECTION

• Infection - begins by HIV-1 with a tropism for
  macrofages
• - the membrane molecules of dendritic cells
  bind
• glycoproteins on HIV-1 surface and transport
  viruses to the lymphatic nodes (LN), where
  activated T cells are infected viruses
  are replicated in the lymphatic nodes and
  transfer to the blood
• features malaise, fever, pain of muscles and
  joints, sweating, loss of appetite, vomiting,
  diarrhoea, rash, lymphadenopathy
• Immunological findings elevated C-reactive
  protein, lymphopenia, decrease of CD4 cells
• specific antibodies against HIV-1 dont generate
• identification of viruses is performed by PCR or
  by the evidence of viral protein p24 presence

25
ASYMPTOMATIC PERIODE

• asymptomatic period HIVs-1 with a tropism for
  macrophages are changed into viruses with a
  tropism for T cells and demage T cells (CD4)
• viruses replicate in cell secondary lymphatic
  organs
• - the period can last a several years
• lasting depends on
• - virus doses and virulence
• - an individual condition of immune system
  an infected
• person
• - an acceleration occures by repeated
  infection of
• different HIVs

26
AIDS

• AIDS- Related Complex (ARC) presents with
  lymphadenopathy and comes before fully developed
  AIDS
• Clinical features of AIDS
• - candidiasis of mouth and esophagous
• mucose, colpitis
• - oral leucoplakia, opportunistic
  infections
• - Kaposi sarcoma, non-Hodgkins lymfoma

27
VACCINE

• development of a vaccine is unsuccessful
• due to
• - unsuccesful searching for a dominant
  viral antigen
• - variability of the viruses HIV-1 in the
  course of time
• - absence of an animal experimental model
  (even the
• primates infection course isnt
  identical with human)

28
TREATMENT

• Inhibitors of reverse transcriptase - 2 types
• Inhibitor of viral protease
• Therapy result to the inhibition of DNA
  synthesis, stop the progress of the disease and
  prolong the life of HIV infected persons

29
IMMUNOGLOBULIN REPLACEMENT THERAPY

• Indication
• Contra-indication
• Adverse reaction

30
IVIG is approved for treating

• X-linked Bruton agammaglobulinemia
• Common Variable ImmunoDeficiency
• others

31
CONTRA-INDICATIONS

• Repeated severe side effects
• Selective IgA deficiency with anaphylactic
  reaction to immunoglobuline
• Severe acute infection

32
IG ADMINISTRATION

• Intramuscullar maximum dose 1,5 g IgG/ week
• Subcutaneous total dose/month 400mg/kg,
  administration every week
• Intravenous - 400 mg/kg/month

33
AUTOIMMUNE DISORDERS

• examples

34
CLINICAL CATEGORIES

• systemic
• - affect many organs and tissue
• organ localised
• - affect predominantly one organ accompained
  by affection of other organs (nonspecific bowel
  diseases, celiatic disease, AI hepatitis,
  pulmonary fibrosis)
• organ specific
• - affect one organ or group of organs
  connected with development or function

35
EXAMPLES OF SYSTEMIC AUTOIMMUNE DISEASES

• examples
• autoantibodies

36
SYSTEMIC AUTOIMMUNE DISEASES

• Systemic lupus erythematosus
• Rheumathoid arthritis
• Sjögrens syndrome
• Dermatopolymyositis
• Systemic sclerosis
• Mixed connective tissue disease
• Antiphospholipid syndrome
• Vasculitis
• Sarcoidosis

37
SYSTEMIC LUPUS ERYTHEMATOSUS

• chronic, inflammatory, multiorgan disorder
• predominantly affects young women
• autoantibodies react with nuclear material and
  attack cell function, immune complexes with
  dsDNA deposit in the tissue
• general symptoms include malaise, fever, weight
  loss
• multiple tissue are involved including the skin,
  mucosa, kidney, joints, brain and cardiovascular
  system
• characteristic features butterfly rash, renal
  involvement, CNS manifestation, pulmonary
  fibrosis

38
DIAGNOSTIC TESTS

• a elevated ESR (erythrocyte sedimentation rate),
  low CRP, trombocytopenia, leukopenia, hemolytic
  anemia, depresed levels of complement (C4, C3),
  elevated serum gamma globulin levels

39
AUTOANTIBODIES

• Autoantibodies ANA, dsDNA (double-stranged), ENA
  (SS-A/Ro, SS-A/La), Sm, against histones,
  phospholipids

40
RHEUMATOID ARTHRITIS

• chronic, inflammatory joint disease with systemic
  involvement
• predominantly affects women
• characterized by an inflammatory joint lesion in
  the synovial membrane, destruction of the
  cartilage and bone, results in the joint
  deformation
• clinical features arthritis, fever, fatigue,
  weakness, weight loss
• systemic features vasculitis, pericarditis,
  uveitis, nodules under skin, intersticial
  pulmonary fibrosis
• diagnostic tests elevated C- reactive protein
• and ESR, elevated serum gammaglobulin levels
• - autoantibodies against IgG rheumatoid
  factor
• (RF), a-CCP (cyclic citrulline peptid), ANA
  
• - X-rays of hands and legs- show a
  periarticular
• porosis, marginal erosion

41
Antiphospholipid syndrome

• autoimmune disease characterized by vein and
  arterial thrombosis, repeated abortions
• accompanied by anti-phospholipid autoantibodies
  (APA) and antibodies against ß2-glykoprotein I

42
EXAMPLES OF ORGAN- SPECIFIC AUTOIMMUNE DISEASES

• diseases
• autoantibodies

43
ORGANOLEPTIC AUTOIMMUNE DISEASES

• Ulcerative colitis
• Crohns disease
• Coeliac disease
• Autoimmune hepatitis
• Primary biliary cirhosis
• Primary sclerotic cholangoitis
• Pulmonary fibrosis

44
Ulcerative colitis

• chronic inflammation of the large intestine
  mucose and submucose
• features diarrhea mixed with blood and mucus
• extraintestinal features (artritis, uveitis)
• autoantibodies against pANCA, a- large intestine

45
Crohns disease

• the granulomatous inflammation of all intestinal
  wall with ulceration and scarring that can result
  in abscess and fistula formation
• the inflammation of Crohn's disease the most
  commonly affects the terminal ileum, presents
  with diarrhea and is accompanied by
  extraintestinal features - iridocyclitis,
  uveitis, artritis, spondylitis
• antibodies against Saccharomyces cerevisiae
  (ASCA), a- pancreas

46
Coeliac disease

• a malabsorption syndrome characterized by marked
  atrophy and loss of function of the villi of the
  jejunum
• inflammatory bowell disease arise from gliadin
  exposition
• autoantibodies against endomysium, the most
  specific tissue transglutaminaze antibodies
  against gliadin are nonspecific
• biopsy of the jejunum with findings of the villi
  atrophy

47
ORGAN SPECIFIC AUTOIMMUNE DISEASES

• Autoimmune endocrinopathy
• Autoimmune neurological diseases
• Autoimmune cytopenia
• Autoimmune cutaneous diseases
• Autoimmune eye diseases

48
AUTOIMMUNE ENDOCRINOPATHY

• Hashimotos thyroiditis
• Graves-Basedow disease
• Postpartum thyroiditis
• Diabetes mellitus I. type
• Addisons disease
• Autoimmune polyglandular syndrome
• Pernicious anemia

49
Hashimotos thyroiditis

• thyroid disease result to hypothyroidism on the
  base of lymphocytes and plasma cells infiltrate
• autoantibodies against thyroidal peroxidase
  (a-TPO) and/or against thyroglobulin (a-TG)

50
Graves disease

• thyrotoxicosis from overproduction of thyroid
  hormone (patient exhibit fatigue, nervousness,
  increased sweating, palpitations, weight loss,
• exophtalmos)
• autoantibodies against thyrotropin receptor,
• autoantibodies cause thyroid cells
  proliferation

51
Diabetes mellitus (insulin- dependent)

• characterized by an inability to process sugars
  in the diet, due to a decrease in or total
  absence of insulin production
• results from immunologic destruction of the
  insuline- producing ß-cells of the islets of
  Langerhans in the pancreas
• autoantibodies against GAD- glutamic acid
  decarboxylase primary antigen), autoantibodies
  anti- islet cell, anti- insulin
• islets are infiltrated with B and T cells

52
AUTOIMMUNE NEUROPATHY

• Guillain-Barré syndrome (acute idiopathic
  polyneuritis)
• Myasthenia gravis
• Multiple sclerosis

53
Myasthenia gravis

• chronic disease resulting from faulty
  neuromuscular transmission
• characterized by muscle weakness and fatigue
• the muscle weakness and neuromuscular
  dysfunction result from blockage and depletion of
  acetylcholin receptors at the myoneural junction
• immunological findings autoantibodies against
  Ach receptors
• ptosis of the eye

54
Multiple sclerosis

• chronic demyeline disease with abnormal reaction
  T cells to myeline protein on the base of
  mimicry between a virus and myeline protein
• features weakness, ataxia, impaired vision,
  urinary bladder dysfunction, paresthesias, mental
  abberations
• autoantibodies against MOG (myelin-oligodendrocyt
  e glycoprotein)
• Magnetic resonance imaging of the brain and spine
  shows areas of demyelination
• The cerebrospinal fluid is tested for oligoclonal
  bands, can provide evidence of chronic
  inflammation of the central nervous system

55
IMMUNOSUPRESSION

• non-specific treatment
• examples of drugs
• indication
• risks

56
Immunosuppressants

• are drugs that inhibit or prevent activity of the
  immune system
• They are used in immunosuppressive therapy to
• Prevent the rejection of transplanted organs and
  tissues
• Treat autoimmune diseases
• Treat some other non-autoimmune inflammatory
  diseases (allergic asthma, atopic eczema)

57
Glucocorticoids

• suppress the cell-mediated immunity
• cytokine production
• suppress the humoral immunity
• side-effects hypertension, dyslipidemia,
  hyperglycemia, peptic ulcers, osteoporosis,
  disturbed growth in children

58

• Drugs affecting the proliferation of both T cells
  and B cells - Cyclophosphamide, Methotrexate,
  Azathioprine, Mycophenolate mofetil
• Drugs blocking the activation of lymphocytes
  Tacrolimus, Sirolimus, Cyclosporin A
• Monoclonal antibodies - Daclizumab